The main goal of this project is to examine sex differences in cocaine cessation and relapse through treatment with exogenous progesterone (PRO) compared to placebo, and to examine impulsivity as a moderating variable by the addition of atomoxetine (ATOM) to PRO. In females, both human and animal studies demonstrate a more rapid progression to dependence, poorer outcomes, and greater effect of cocaine; sex hormones likely play a prominent role (Hyman et.al., 2008, Tuchman, 2010). PRO is of interest because of its attenuation of subjective effects of cocaine (Sofuogu 2004) and craving (Specker 2010) as well as its potential impact on impulsivity. Impulsivity is clearly associated with risk for addiction. Atomoxetine s chosen because of the finding of improvement in impulsivity tasks in animals (Robinson, 2008). Here we will examine the interplay of PRO, impulsivity and sex differences in drug taking and cessation while examining effects of ATOM on impulsivity. Cocaine dependent + nicotine dependent females and males will be studied in a double blind randomized trial with three groups: PRO/Placebo, PRO+ATOM/Placebo, and Placebo/Placebo. Cocaine and nicotine dependence coexist and have many commonalities; hence we propose to study this population. The overall design parallels Project I and provides a unique opportunity to study both cocaine and nicotine and delineate sex differences. RELEVANCE (See instructions): Despite much effort, there are not yet highly effective approved medications for the direct treatment of cocaine and nicotine dependence. This SCOR will carry out interdisciplinary and translational investigations to identify pharmacological interventions targeting behaviors impaired in nicotine and cocaine dependent subjects to enhance the effectiveness of existing behavioral treatments for addiction. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/